We here report a patient with metastatic RCC who developed severe sunitinib-induced toxicities, including hypertension, high fever, liver dysfunction, and thrombocytopenia, after only 10 days administration of sunitinib. Despite immediate discontinuation of sunitinib, these symptoms persisted for over a week, and subsequent life-threatening hypoxia due to pleural effusion and pulmonary edema occurred. A phase I dose-escalation study of sunitinib administered daily on a 4-weeks-on, 2-weeks-off schedule indicated that most patients with a dose-limiting toxicity (DLT), including thrombocytopenia, hypertension and asthenia, had a combined (sunitinib plus SU012662) trough plasma concentration of ≥1mL/mL [
12]. The combined plasma concentration of sunitinib and SU12662 on day 14 in this case was 160.3 ng/mL, even when measured at 3 days after the discontinuation of sunitinib.
Several factors can be attributed to the pathogenesis of the significantly high plasma concentrations of sunitinib and SU12662. First, co-administration of sunitinib with strong inhibitors of
CYP3A4 and/or intake of grapefruit increase sunitinib concentration; however, our patient did not take these in parallel with sunitinib treatment. Second, we assumed that the patient might be a carrier of the variant alleles of SNPs in
CYP3A5,
ABCB1, and/or
ABCG2 that cause higher plasma concentrations of sunitinib.
ABCG2, the so-called breast cancer resistance protein (BCRP), is an ATP-binding cassette (ABC) drug transporter that facilitates the efflux of various tyrosine kinase inhibitors, including sunitinib, from cells. The
ABCG2 421C > A polymorphism is associated with reduced ABCG2 protein expression and/or activity [
13]. The reduced protein levels of the AA genotype in
ABCG2 421C > A in the apical membranes of small intestinal enterocytes, hepatocytes, and renal proximal tubule epithelial cells might affect intestinal absorption and/or elimination after oral administration of sunitinib, leading to extremely high systemic exposure to sunitinib. Kim et al. reported that the
ABCG2 421 AA genotype is mostly associated with the risk of sunitinib-related toxicities, such as thrombocytopenia, neutropenia and hand–foot syndrome, in Korean patients with metastatic RCC; however, the pharmacokinetics data was not shown [
5]. Mizuno et al. reported a Japanese case with the
ABCG2 421 AA genotype that developed severe toxicities due to high exposure of sunitinib and SU12662 [
14]. Additionally, they demonstrated the
ABCG2 421A > C genotype as a significant covariate associated with lower oral clearance by generating a population pharmacokinetics model of sunitinib from 19 Japanese patients with RCC, in which the number of patients with
ABCG2 421 CC, CA and AA genotypes were 10, 8, and 1, respectively. The plasma concentration–time profiles simulated with repeated sunitinib doses of 50 mg/day based on the model showed that trough concentrations after 14 days for most
ABCG2 421C > A carriers exceed 100–130 ng/mL [
15]. However, the plasma concentration of sunitinib in our patient on day 14, when the administration of sunitinib has been discontinued for three days after repeated doses of 50 mg/day, was 131.9 ng/mL.
The elimination half-life of sunitinib calculated from its plasma concentrations on days 14, 16, 18, 20, and 22 in our patient was 50.1 hours, similar to that previously reported (41–86 hours) [
12]. Therefore, it could be explained that the high exposure of sunitinib was caused by the loss of ABCG2 protein expression by genetic polymorphism. In the present study, the genotypes of SNPs in
CYP3A5 and
ABCB1, which are potentially related to the pharmacokinetics of sunitinib [
7‐
11], were heterozygous for the variant alleles, indicating that these SNPs might also be involved in the high systemic exposure of sunitinib to the patient.
Another population pharmacokinetics study also identified ethnic background as a significant covariate for the prediction of oral clearance [
16]. The frequency of the
ABCG2 421 AA genotype is higher in Asian populations (Japanese, 7% [
13]; Korean, 8% [
17]; and Chinese, 12% [
18]) than in non-Asian populations (Caucasian, 1.7% and African, 0.2% [
18]). Thus, this racial difference in the frequency of the
ABCG2 421 AA genotype could explain the higher frequency of grade 3 and 4 sunitinib-related toxicities in Asians than in non-Asians [
19,
20].
Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions develop in Asians treated with sunitinib.